Volume 19, Issue 10 p. 1146-1157
Research Article

Distribution, type, and origin of Parkin mutations: Review and case studies

Katja Hedrich PhD

Katja Hedrich PhD

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Human Genetics, University of Lübeck, Lübeck, Germany

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Cordula Eskelson MD

Cordula Eskelson MD

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Human Genetics, University of Lübeck, Lübeck, Germany

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Beth Wilmot MS

Beth Wilmot MS

Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland Oregon, USA

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Karen Marder MD, MPH

Karen Marder MD, MPH

Department of Neurology, Columbia University, New York, New York, USA

Gertrude H. Sergievsky Center, New York, New York, USA

Taub Institute for Research on Alzheimer's disease and the Aging Brain, New York, New York, USA

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Juliette Harris PhD

Juliette Harris PhD

Department of Neurology, Columbia University, New York, New York, USA

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Jennifer Garrels BS

Jennifer Garrels BS

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Human Genetics, University of Lübeck, Lübeck, Germany

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Helen Meija-Santana MS

Helen Meija-Santana MS

Department of Neurology, Columbia University, New York, New York, USA

Gertrude H. Sergievsky Center, New York, New York, USA

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Peter Vieregge MD

Peter Vieregge MD

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Neurology, Hospital Lippe-Lemgo, Germany

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Helfried Jacobs MD

Helfried Jacobs MD

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Neurology, Hospital Rothenburg/Wümme, Germany

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Susan B. Bressman MD

Susan B. Bressman MD

Department of Neurology, Beth Israel Medical Center, New York, New York, USA

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Anthony E. Lang MD

Anthony E. Lang MD

Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Toronto Western Hospital, Toronto, Ontario, Canada

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Martin Kann MD

Martin Kann MD

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Human Genetics, University of Lübeck, Lübeck, Germany

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Giovanni Abbruzzese MD

Giovanni Abbruzzese MD

Department of Neurological Sciences and Vision, University of Genova, Genova, Italy

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Paolo Martinelli MD

Paolo Martinelli MD

Department of Neurological Sciences, University of Bologna, Bologna, Italy

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Eberhard Schwinger MD

Eberhard Schwinger MD

Department of Human Genetics, University of Lübeck, Lübeck, Germany

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Laurie J. Ozelius PhD

Laurie J. Ozelius PhD

Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, USA

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Peter P. Pramstaller MD

Peter P. Pramstaller MD

Department of Neurology, Regional General Hospital, and EURAC-Research, Genetic Medicine, Bolzano, Italy

Department of Neurology, Oregon Health and Sciences University, Portland, Oregon, USA

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Christine Klein MD

Corresponding Author

Christine Klein MD

Department of Neurology, University of Lübeck, Lübeck, Germany

Department of Human Genetics, University of Lübeck, Lübeck, Germany

Department of Neurology, University of Lübeck; Ratzeburger Allee 160, 23538 Lübeck, GermanySearch for more papers by this author
Patricia Kramer PhD

Patricia Kramer PhD

Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland Oregon, USA

Department of Neurology, Oregon Health and Sciences University, Portland, Oregon, USA

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First published: 09 July 2004
Citations: 172

Abstract

Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type. © 2004 Movement Disorder Society